Inflammatory disorders account for a significant amount of debilitating diseases. Inflammatory states, such as arthritis, psoriasis, asthma, and possibly atherosclerosis, stem from inflammatory reactions in the joints, skin, and blood vessels. It is generally believed that a central role in the inflammatory reaction is the production of phospholipid metabolites called eicosanoids. The eicosanoids represent a family of important mediators such as the leukotrienes, prostaglandins, lipoxins, hydroxyeicosatetranoic acid, and thromboxanes. It is believed that the generation of eicosanoids is dependent on the availability of arachidonic acid which is liberated from phospholipids by the action of phospholipase A.sub.2 (PLA.sub.2).
PLA.sub.2 is the common name for phosphatide 2-acylhydrolase, which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides which results in the production of equimolar amounts of lysophospholipids and free fatty acids [Dennis, E. A., The Enzymes, Vol. 16, Academic Press, New York, (1983)]. PLA.sub.2 enzymes are found in all living species and form a diverse family of enzymes. Over forty PLA.sub.2 enzymes have been structurally characterized, and they show a high degree of sequence homology. [J. Chang, J. H. Musser, and H. McGregor, "Phospholipase A.sub.2 : Function and Pharmacological Regulation," Biochem. Pharm. 36: 2429-2436, (1987)].
The best characterized varieties of PLA.sub.2 enzyme are the secreted forms, which are released into the extracellular environment where they aid in the digestion of biological materials. The secreted forms have a mw of about 12-15,000 (Chang, et al, supra). In contrast, cytosolic PLA.sub.2 s are found in small amounts within the cell and play a key role in the biosynthetic pathway leading to the formation of the platelet activating factors and the eicosanoids. [Mobilio, D. and Marshall, L. A. , "Recent Advances in the Design and Evaluation of Inhibitors of Phospholipase A.sub.2, " Ann. Reports in Med. Chem. 24; 157-166, (1989)]. The cytosolic PLA.sub.2 s have a mw of approximately 85,000. [Clark, J. D., Lin, L. L., Kriz, W., Ramesha, C. S., Sultzman, Lin, A. Y., Merlona, N., Knots, J. L., Cell 65: 1043-1051 (1991)]. Free arachidonic acid is the rate limiting precursor for the production of eicosanoids and is liberated from its membrane phospholipid store by the action of cytosolic PLA.sub.2. [Dennis, E. A., "Phospholipase A.sub.2 Mechanism: Inhibition and Role in Arachidonic Acid Release," Drug Dev. Res. 10: 205-220, (1987)]. The same enzymatic step also produces lysophospholipids which may be converted to form platelet-activating factors. Thus, it is believed that cytosolic PLA.sub.2 is central to the regulation of the biosynthetic pathways of potent lipid mediators of inflammation.
Due to the central role in the inflammation process that is played by cytosolic PLA.sub.2, it is desirable to identify and characterize new inhibitors of the enzyme. Such inhibitors may lead to new therapies for the treatment of arthritis, asthma, atherosclerosis, and inflammatory diseases of the skin (e.g. psoriasis) and the bowel (e.g. irritable bowel syndrome). Identification of such specific PLA.sub.2 inhibitors may aid the medical community in reaching the goal of control of inflammatory disease states.